The present invention pertains to a method for activating the immune system of a patient by intermittently administering interleukin-2 (IL-2) to that patient. Such administration of IL-2 can optionally be combined with other therapies, e.g., anti-retroviral, anti-bacterial, or anti-fungal therapies, suitable for treatment of the patient's condition. This invention also relates to an approach to gene therapy that entails the use of IL-2 given to a patient so as to facilitate in situ lymphocyte transduction by a retroviral vector also administered to the same patient.
Attempts at immune activation and restoration in the past have utilized bone marrow transplantation or lymphocyte transfers (H. C. Lane et al., Ann. Internal Med. 113: 512-519 (1990)), immunomodulating agents such as immuthiol (J. M. Lang et al., Lancet 24: 702-706 (1988)) or isoprinosine (C. Pedersen et al., N. Engl. J. Med. 322: 1757-1763 (1990)), and recombinant cytokines such as interferon alpha (IFN-.alpha.) (H. C. Lane et al., Ann. Intern. Med. 112: 805-811 (1990)) or IL-2. H. C. Lane et al., J. Biol. Response Mod. 3, 512-516 (1984); D. H. Schwartz et al., J. Acquir. Immune Defic. Syndr. 4, 11-23 (1991); P. Mazza et al., Eur. J. Haematol. 49: 1-6 (1992); H. W. Murray et al., Am. J. Med. 93: 234 (1992); H. Teppler et al., J. Infect. Dis. 167: 291-298 (1993); P. Volherding et al., AIDS Res. Hum. Retroviruses 3: 115-124 (1987). These studies have resulted in minimal or transient immune system restoration.
The use of biologic response modifiers in general, and of IL-2 in particular, is an active area of clinical research. Interleukin-2 is a T cell-derived lymphokine with a number of immunomodulating effects including activation, as well as induction of proliferation and differentiation, of both T and B lymphocytes (K. A. Smith, Science 140: 1169-1176 (1988)). Exogenous IL-2 has been shown in vitro to increase the depressed natural killer cell activity and cytomegalovirus-specific cytotoxicity of peripheral blood mononuclear cells from patients with AIDS (A. H. Rook et al., J. Clin. Invest. 72: 398-403 (1983)), as well as to increase IFN-.gamma. production by lymphocytes from patients with AIDS (H. W. Murray et al., Ioc. cit. 76: 1959-1964 (1985)).
IL-2 given by high dose infusion has been employed in the treatment of renal cell carcinoma and melanoma (J. Natl. Cancer Inst. 85(8): 622-632 (1993)). For example, doses of 36 million international units (MU) given continuously over a period of 24 hours has been used in the treatment of cancer (18MU is equivalent to about 1 mg protein). Lancet 340: 241 (1992). The use of high doses of IL-2 generally is not well tolerated by patients, however, and side effects are more pronounced at such high levels.
Other researchers are evaluating IL-2 in the treatment of other diseases, including HIV infection. The use of lower doses of IL-2 in a continuous therapy regime has been disclosed by Yarchoan et al., U.S. Pat. No. 5,026,687. More specifically, Yarchoan et al. teach the use of the anti-retroviral agent ddI in combination with IL-2 administered continuously at a dosage between 25,000 to 1 million international units (U) per day, for a period of three months. While Yarchoan et al. predict that "beneficial results" will accompany the combined ddI/IL-2 regimen, they do not attribute these results to IL-2 per se. Moreover, although dosages at this lower level have been shown to cause initial increases in CD4 levels, these increases were transient in nature, i.e., CD4 levels returned to baseline within 6 months after the completion of the treatment.
Many researchers feel that the use of IL-2 is contraindicated in patients with HIV infection due to its potential to activate HIV. No method of treatment of HIV with IL-2 has been disclosed which results in a sustained response, or which yields long-term beneficial results.
Cells that have been stimulated to actively synthesize DNA are susceptible to transduction by gene transfer therapy. Present methods of gene therapy require a complicated, in vitro transformation. More specifically, cells are removed from a patient, activated in vitro, and used to establish cell lines which are then gene-transduced in vitro and reimplanted in the patient. This procedure is expensive, and its success its limited due to the potential of failure at each of the steps of activating the cells, effecting the transduction, and implanting the cells in the patient for expression.
Attempts at using retroviral vectors to effect in vivo gene transfer have been limited. Retroviruses will only integrate stably into target cells that are actively synthesizing DNA. This integration must occur before retroviral gene expression can be effected. Because only a fraction of cells are actively producing DNA at any giving time, such in vivo gene transfer methods have shown little success.